Fabrication of micro/nanoparticles of drugs for pharmaceutical applications

Many drugs are of very poor water solubility, so they tend to be eliminated from the gastrointestinal tract before they could be absorbed into the blood circulation. This results in low bioavailability and poor dose proportionality, and therefore leads to an overall inefficient treatment for the patients. Modifications to the drug substance itself and the creation of specific formulations have been used to enhance the dissolution rate as well as bioavailability of poorly water soluble drugs. Physical modifications to increase the surface area, solubility and wettability of the drug particles typically focus on particle size reduction and generation of amorphous states. In this study, the particle size of several poorly water soluble drugs (artemisinin, quercetin, curcumin, glibenclamide, hesperetin, silymarin) was successfully reduced by employing three fabrication methods namely, spray drying, antisolvent precipitation with a syringe pump (APSP), and evaporative precipitation of nanosuspension (EPN). The hydrophilic carriers like polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG) were also used in the fabrication processes in order to understand their effect on formation of drug particles. A percent dissolution surface-response model was regressed and statistically assessed to understand the direct relationships between the process parameters on one hand and percent dissolution on the other. Firstly, the microparticles of poorly water soluble drug, artemisinin, were produced by the modified spray drying and the particle size was further reduced by using the improved APSP method. Later micro/nanoparticles of quercetin, curcumin, glibenclamide and hesperetin were also prepared by the APSP method. Finally, the nanoparticles of all the drugs used in this study were successfully prepared by the newly developed EPN method. The dissolution rate of the drug nanoparticles prepared by the EPN method exhibited many folds increase in the dissolution rate of the drugs. The APSP and EPN method developed in this study have been found to be effective in decreasing the particle size of drugs and hence, increasing their dissolution rate. These methods also have advantages such as being less energy intensive and less time consuming, using low-cost set up and low temperature and pressure conditions, which protect sensitive drugs. Moreover, no impurities are introduced and no toxic surfactants or stabilisers are used. In the next stage, drug dispersions in a carrier matrix were prepared with the aim to reduce the particle size down to the molecular level. The binary dispersions of the drugs, curcumin and hesperetin, in the polymer (PVP or PEG) matrix were prepared which showed the better dissolution than the plain drug nanoparticles. The dispersions were further improved by adding surfactants (F38, F127, T20, T80), and the ternary dispersions thus formed presented higher dissolution rates and were physically more stable than the binary dispersions. The Korsemeyer–Peppas and Weibull models were used to study the drug release kinetics from the drug dispersions and diffusion was found to be the key release mechanism. Drug dispersions have been widely used for dissolution enhancement of poorly water soluble drugs but the ternary dispersions are yet to be fully explored and provide a potential improvement over the existing formulations in terms of dissolution and physical stability of drug. The enhanced dissolution of the drug nanoparticles and dispersions can potentially translate into an increased bioavailability in-vivo. This will lead to considerable dose reduction for patients. To conclude, these drug nanoparticles and dispersions produced by systematic methods in this study would have high potential for delivery in much smaller doses compared with commercial preparation containing the normal form of the drug.Doctor of Philosophy (MAE

Carbon nanomaterials for drug delivery

Carbon Nanotubes (CNTs) and Graphene Have Attracted Tremendous Attention as the Most Promising Carbon Nanomaterials in the 21st Century for a Variety of Applications such as Electronics, Biomedical Engineering, Tissue Engineering, Neuroengineering, Gene Therapy and Biosensor Technology. For the Biomedical Applications, Cnts Have Been Utilized over Existing Drug Delivery Vectors due to their Ability to Cross Cell Membranes Easily and their High Aspect Ratio as Well as High Surface Area, which Provides Multiple Attachment Sites for Drug Targeting. Besides, it Has Also Been Proved that the Functionalization of CNTs May Remarkably Reduce their Cytotoxic Effects and at the Same Time Increase their Biocompatibility. So, the Functionalized CNTs Are Safer than Pristine or Purified CNTs, Thus Offering the Potential Exploitation of Nanotubes for Drug Administration. On the other Hand, More Recently Graphene and its Derivatives Have Been Enormously Investigated in the Biological Applications because of their Biocompatibility, Unique Conjugated Structure, Relatively Low Cost and Availability on both Sides of a Single Sheet for Drug Binding. In Our Study, we Have Covalently Functionalized Multiwalled Carbon Nanotubes (MWCNTs) and Graphene Oxide (GO) with Highly Hydrophilic and Biocompatible Excipients in Order to Increase their Aqueous Solubility and Biocompatibility. Various Excipients Used Were Polyvinyl Alcohol, Pluronic F38, Tween 80 and Maltodextrin. The Poorly Water-Soluble Anticancer Drugs such as, Camptothecin and Ellagic Acid, Were Loaded onto the Functionalized MWCNTs and GO via Non-Covalent Interactions. Furthermore, Drug Loading and Cytotoxic Activity of Drugs Incorporated with the Functionalized MWCNTs and GO as Nanocarriers Were Also Investigated. Drugs Loaded on both Carbon Nanocarriers Exhibited a Higher Cytotoxic Activity than Free Drug. On the other Hand, No Significant Toxicity Was Found even at Higher Concentrations when the Cells Were Incubated with the Functionalized Mwcnts and GO. Therefore, both these Functionalized Carbon Nanomaterials Are Ideal Carriers for Drug Delivery

Ternary dispersions to enhance solubility of poorly water soluble antioxidants

The main aim of this study was to enhance the solubility and dissolution rate of the two poorly water-soluble antioxidants, curcumin (CUR) and hesperetin (HSP). Binary dispersions of the two drugs in the polymer, polyvinylpyrrolidone (PVP) or polyethylene glycol (PEG) matrix were prepared. A surfactant (Pluronic F127 or Tween 80) was also combined with the polymer to develop ternary solid dispersions to further improve the dissolution properties of CUR and HSP. The FTIR study suggested hydrogen bonding between PVP and the drugs and minor intermolecular interactions between PEG and drugs. PVP showed better amorphizing nature than PEG as inferred from the DSC and XRD study. The surfactants added in the ternary dispersions further enhanced the intermolecular interaction of the polymers with the drugs. The 2D micro-Raman spectroscopic mapping showed that after adding the surfactants in the ternary dispersions, CUR and HSP were more uniformly distributed in the PEG matrix. The solubility and dissolution rates of CUR and HSP were increased by dispersing them in the polymer matrix and the increase was dramatic when the surfactant was added to the dispersion system. The intermolecular interactions between drug and carriers led to better dispersion of drug in the polymer matrix and reduction in the size of drug particles; increase in the amorphous nature, decrease in surface tension and increase in the wettability which resulted in enhanced solubility and dissolution of the ternary dispersions. The ternary dispersions also presented better long term stability in terms of the amorphous nature and the dissolution properties

Preparation of nanoparticles of poorly water-soluble antioxidant curcumin by antisolvent precipitation methods

The objective of this study was to enhance the solubility and dissolution rate of a poorly water-soluble antioxidant, curcumin, by fabricating its nanoparticles with two methods: antisolvent precipitation with a syringe pump (APSP) and evaporative precipitation of nanosuspension (EPN). For APSP, process parameters like flow rate, stirring speed, solvent to antisolvent (SAS) ratio, and drug concentration were investigated to obtain the smallest particle size. For EPN, factors like drug concentration and the SAS ratio were examined. The effects of these process parameters on the supersaturation, nucleation, and growth rate were studied and optimized to obtain the smallest particle size of curcumin by both the methods. The average particle size of the original drug was about 10–12 μm and it was decreased to a mean diameter of 330 nm for the APSP method and to 150 nm for the EPN method. Overall, decreasing the drug concentration or increasing the flow rate, stirring rate, and antisolvent amount resulted in smaller particle sizes. Differential scanning calorimetry studies suggested lower crystallinity of curcumin particles fabricated. The solubility and dissolution rates of the prepared curcumin particles were significantly higher than those the original curcumin. The antioxidant activity, studied by the DPPH free radical-scavenging assay, was greater for the curcumin nanoparticles than the original curcumin. This study demonstrated that both the methods can successfully prepare curcumin into submicro to nanoparticles. However, drug particles prepared by EPN were smaller than those by APSP and hence, showed the slightly better solubility, dissolution rate, and antioxidant activity than the latte

Fabrication of quercetin nanoparticles by anti-solvent precipitation method for enhanced dissolution

The aim of this study was to enhance the dissolution rate of a poorly water-soluble drug quercetin by fabricating its nanoparticles with anti-solvent precipitation using the syringe pump and to investigate the effect of drug concentration, solvent to anti-solvent (S/AS) ratio, stirring speed and flow rate on the particle size. Characterization of the original quercetin powder and nanoparticles made by syringe pump was carried out by the scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and dissolution tester. The results indicated that decreasing the drug concentration, increasing the stirring speed, flow rate and the S/AS volume ratio favoured the reduction in the particle diameter to ∼ 170 nm. Percent dissolution efficiency (%DE); relative dissolution (RD); mean dissolution time (MDT); difference factor (f1) and similarity factor (f2) were calculated for the statistical analysis. The dissolution of the drug nanoparticles was significantly higher compared with the pure drug in simulated intestinal fluid (SIF, pH 6.8)

Long-term stability of quercetin nanocrystals prepared by different methods

Objectives  This study aimed to examine the long-term physical stability of quercetin nanocrystals produced by three methods. Methods  Quercetin nanocrystals were prepared by high pressure homogenization, bead milling and cavi-precipitation. The nanocrystals produced by these methods were compared for particle size, saturation solubility and dissolution of the drug particles, and were subjected to stability testing. Key findings  The X-ray diffraction study and microscopic pictures taken under polarized light indicated the crystalline nature of the nanocrystals produced by the three methods. As the crystalline state is relatively more stable than the amorphous state, a good physical stability was expected from the quercetin nanocrystals prepared. The high-pressure homogenized and bead-milled quercetin nanocrystals showed excellent physical stability when stored under refrigeration (4 ± 2°C) and at room temperature (25 ± 2°C) for 180 days. The dissolution properties were not significantly affected on storage at room temperature. However, increase in the storage temperature to 40 ± 2°C led to physical instability. On the other hand, the cavi-precipitated quercetin nanocrystals exhibited a lower stability than the bead-milled and homogenized formulations and did not show the optimum zeta potential values as well. In the case of cavi-precipitated nanocrystals, recrystallization and agglomeration were responsible for the increasing particle size besides the Ostwald ripening phenomenon. The solvents used during cavi-precipitation might have competed with the surfactant for hydration leading to a partial dehydration of the surfactant, which subsequently affected the stability of the quercetin nanocrystals. Conclusions  High-pressure homogenized and bead-milled quercetin nanocrystals showed better physical stability than the cavi-precipitated ones. Freeze drying immediately after nanocrystal production can help to prevent their agglomeration and thus improve physical stability

Fabrication of quercetin nanocrystals : comparison of different methods

The main aim of this study was to prepare quercetin nanocrystals using three fabrication methods, viz. high-pressure homogenization, bead milling, and cavi-precipitation. The three fabrication methods were compared in terms of particle size, saturation solubility, and dissolution of the products obtained. The average particle size of the coarse quercetin was 50.1 μm. The three methods produced quercetin particles in the nanometre range (276–787 nm) and the smallest nanocrystals of around 276.7 nm were fabricated by bead milling. The particle size, polydispersity index, zeta potential, and saturation solubility values for the products fabricated by both high-pressure homogenization and bead mill were similar and thus both represented an efficient means to fabricate quercetin nanosuspensions. According to X-ray diffraction analysis, all nanocrystals were still in the crystalline state after being fabricated by the three methods. The cavi-precipitated product exhibited larger particle size and did not show an optimum stability as suggested by the zeta potential values. However, cavi-precipitated quercetin nanosuspension showed the higher saturation solubility due to the presence of ethanol. The bead milled products with the lowest particle size exhibited a saturation solubility of 25.59 ± 1.11 μg/ml, approximately nine times higher than coarse quercetin. Overall, the dissolution rates of the quercetin nanosuspensions fabricated by these three methods enhanced compared to the coarse quercetin